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Update on HPV: Beyond cervical cancer

Joel Palefsky, MD
University of California
Division of Infectious Diseases
San Francisco, California

Good afternoon. So I’m going be bring up the rear this afternoon! And talk to you about some of the other body parts that are potentially affected by HPV just to be thinking about because the focus has been so heavily, quite appropriately, on cervical disease. But I think in the next few years, in fact, in the next weeks or so, you’ll start to hear some data about HPV infection and how it might potentially be prevented in some of the other body sites in question. So the topic for my presentation is HPV does not just cause cervical cancer. Dr. Cox started off talking about the cervix, Dr. Haefner about the vulva and the vagina and I’ll be telling you a little bit about the anus and the oral cavity.

So what I’d like to do is talk to you about HPV disease in men because everything you’ve heard about is in women. Talk briefly about penile infection and disease, anal infection and disease and oral infection and disease. And when we talk about oral and anal, for that matter, it’s important to remember that these are two body parts, of course, that don’t belong to any one sex. And then talk to you about how we’re thinking about male vaccination and its affect on disease risk in women. And then potentially the impact on HPV infection to prevent these diseases.

So if you look at the spectrum of HPV related cancers in the United States, clearly the cervix is quite dominant as far as the number of cases is concerned. But there are a number of cases that are attributable to HPV in the oropharynx. Most of the anal cancers are HPV associated. A smaller number of oral cavity and laryngeal cancers and you’ve already heard about the vulva, and in this country the penile rate is not very high.

But just to put this in context, in the U.S. currently there are about 9700 cases of invasive cervical cancer. You heard about 3500 or so die every year.

And if you compare men to women, quite interestingly, when you count up the number of cases in American men associated with HPV it’s remarkably similar to the number of cases of cervical cancer that we see. When you add up the cases in the oral cavity, the oropharynx, the larynx, the anus and the penis, for example. So this is a problem I think we really have to be focusing on more in the future.

So first let’s talk about oral cancer. I think one of the key findings in the last few years has been the appreciation that there are really two kinds of oral cancer. There is the so-called classic oropharyngeal squamous cell cancer, which is typically associated with risk factors such as alcohol and tobacco use. And then there is another kind, which we’re calling non-classical, which is actually thought to be more HPV associated. And what you can see is that over time the HPV associated cancers are increasing in incidence and the classic squamous cell cancers are starting to decline. And we think in a few years actually those curves are going to meet.

So some nice studies done by Maura Gillison and others, for example, showed that if you’re looking at the HPV associated cancers, the risk factors that are important are oral sex primarily, number of partners, whereas tobacco and alcohol are not playing a role. In contrast the classical ones show alcohol and tobacco is the primary risk factors as opposed to more sexual risk factors.

So what about penile cancer? Again, this is not a very common cancer here in the United States but it is more common in those countries where cervical cancer is especially common. In Uganda, for instance, the incidence is about 4 per 100,000 in contrast say to Israel where it’s almost non-existent and it’s thought that one of the most important protective factors there is circumcision.

What about the anus? Again, not something that is on most people’s radar screens but which is assuming increasing importance, I think. The reason the anus is particularly interesting in this context is that it is biologically quite similar to that of the cervix. The transformation zone in the cervix, which is the primary target of HPV has an equivalent in the anal canal, which is where the rectal epithelium meets the anal epithelium. So this anal/rectal junction is a transformation zone and you can do Pap smears and HPV testing and ablations on the anus just like you would in the cervix.

The question is why would you want to do that? And the answer is, number one, in the general population the incidence of anal cancer is increasing amongst both men and women. You can see that in these slides here. It’s going up by about 2% every year in the general population.

And the other is that there are specific target populations that have especially high incidence of HPV related anal cancers. So, again, just to put this in the context of its homologue, the cervix, cervical cancer screening has lead to substantial reduction in cervical cancer. We started off at about 40 to 50 per 100,000. We’re down to about 8 or so per 100,000. If you look at men who have sex with men who are presumably at risk of acquiring HPV through receptive anal intercourse, the incidence of anal cancer prior to the HIV epidemic was, I think, quite similar to what we used to find in the cervix before we were screening there. And as you know we don’t have, yet, a routine screening program for anal disease. If you now throw in immunosuppression on top of that, in this case in the form of HIV positivity, the incidence of anal cancer is estimated to be at least twice as high in this group compared with this group or on the order of about 70 per 100,000. That makes it roughly ten times the current rate of cervical cancer in this country.

In fact, as we have now helped people to live longer through the advent of highly active anti-retroviral therapy, malignancies are now assuming the number one position of causes of mortality in this population. People are living longer, they have more time to develop cancers when they’re not being screened and treated for the pre-cancerous lesions. And three recent cohorts showed, for instance, that the incidence of anal cancer in this post-HAART era has gone up to 75 per 100,000, 137 per 100,000, 78 per 100,000.

So, again, to put these in the context of cervical disease for one more time, this is the age-related cervical cancer incidence worldwide where the highest rates of cervical cancer are seen in the Southern Hemisphere. But they are almost all less than 90 or so per 100,000. We’re now starting to see rates of anal cancer exceeding 100 per 100,000 or more.

And finally, Dr. Haefner, I think nicely outlined the problems associated with genital warts. She focused on men. But more than 10% of men will be diagnosed with warts during their lives, primarily people in the 20 to 29 age group. Again, they’re not going to kill anybody but they’re extremely unpleasant. They’re unsightly. They have a lot of psycho-social stigma and they require a lot of treatments. On average at least three rounds of therapy and they often come back.

So to summarize the burden of HPV infection in men, we have almost 10,000 cases every year of HPV related cancers, primarily in the penis, anus and head and neck area. We didn’t talk much about benign juvenile respiratory papillomatosis but this is devastating consequence of installation of HPV in the larynx at the time of childbirth through aspiration and it requires multiple surgeries in young infants. [466.964] And then roughly 500,000 cases and [469.762] you heard 900,000 from Hope, this is because 500,000 are in the men, the other in the women.

So what about the infection that is responsible for all this mayhem? Well it turns out that if you look for instance at oral HPV infections, it’s not found very commonly, at least the way we sample right now. This is a study showing people, different age groups. You can see in the young babies, even up to 15 years old it’s pretty uncommon and then it goes up a little bit during adolescence but not a whole lot. So we don’t see a lot of oral HPV infection unless you have higher risk populations and that’s shown on this slide.

These were studies from HIV positive women and women who are at high risk of HIV infection. The top two lines are cervical infection. This is the HIV positive women in the cervix, you can see more than 80% have HPV infection over much of their lifetime. It declines in the HIV negative women and here’s oral HPV infection in the HIV positive women and in the HIV negative women it’s much more common than I showed you before in the younger children but on the other hand it remains at least in the HIV positive people substantially rarer than in the cervix.

Now let’s turn to the penis. The data that I’m going to show you on the penis I think you’re going to find remarkably similar to what I’m about to show you a few minutes later in the anus. And they show, for example, that if you sample men in cohort studies, about 60% of them are going to have a detectable HPV type at any one moment in time. The most common site is on the penile shaft followed by the glans and the corona and then progressively rarer and rarer. Interestingly in this study of heterosexual men, people who did not have a history of receptive anal intercourse, roughly 25% of them had infection in the anal canal with HPV.

If you look at the variety of countries it’s pretty similar at that 60% prevalence and if you look at age, it’s also pretty constant throughout the pretty wide age range that we’re seeing here. And this is in very clear contradistinction to what we see in the cervix where the peak prevalence of HPV infection of the cervical in the cervix is typically in the 18 to 24 age group and then it declines very substantially so that most women no longer have detectable HPV after the age of 30. So we’re seeing a very distinct epidemiology of HPV infection on the penis.

And if you look at the risk factors for HPV infection, there’re classic sexual risk factors, increasing number of partners, and this is true for both oncogenic and non-oncogenic types, different number of female partners in the last three months, and then progressively less condom use are all associated with increased risk of penile HPV detection.

If you compared the natural history of penile infection to cervical infection, what’s interesting is that the cumulative risk of getting HPV is not all that different between men and women over roughly similar periods of time. These are two different studies. But interestingly the clearance time is shorter on the penis than it is in the cervix. So it appears that when men get infected they don’t seem to carry the virus as long as women do.

And now, finally in our little HPV survey here I want to tell you about what I think are the most provocative data and that is that virtually everybody who is HIV positive when you’re an MSM, has anal HPV infection and a very high proportion of HIV negative men have sex with men has anal HPV infection, roughly 60%.

And I told you before that the age-related prevalence of penile infection is very similar to that of the anus and that’s shown here. This is an age-related curve of prevalent HPV infection in the anal canal in HIV negative MSM and you can see that it ranges between 50 and 60%, again, throughout the entire age range of the individuals studied. This was a study of about 1400 individuals. And a subset of these, almost 30% in some age groups have the cancer causing HPV types.

So the question that we always get asked is were these very unusual or highly selected patient populations, does that account for the very high rates and the answer is no because we’ve done some population based studies as well. If you focus on this part of the slide here you can see that in these population, true population based data, 57% of the HIV negative men had anal HPV infection and 88% of the HIV positive men had anal HPV infection. So the numbers are very similar to what we saw in our earlier cohort studies.

Now one thing that I think might be of particular interest to this group is the fact that in our earlier studies and confirmed consistently ever since, we have found more anal HPV infection in women than we find in the cervix. We first started with the most immunosuppressed group of people in these studies shown here on the right side of this slide and HIV positive women where it’s shown if you look in yellow, this is the combined anal, 68% of the HIV positive women had anal HPV infection compared with 33% who had cervical. And if you move progressively more towards the so called normal end of the spectrum, here are the high-risk HIV negative women, so these are women with a history of commercial sex work or injection drug use, 31% have anal HPV infection compared to 11% with cervical HPV. And then in a study that we did in a very healthy group of young women in the Dysplasia Clinic at UCSF and at Planned Parenthood, we find that about 60% of them have anal HPV infection compared to about 50% or so in the cervix. And then in a study done in a completely healthy, more or less population based group in Hawaii, it’s about the same. So anal HPV infection is far more common, I think, than anybody might have imagined in women. And what it means, I think still remains to be determined. My own feeling is that it well may be an important reservoir of infection that affects the biology of cervical infection in addition to whatever it might do with respect to anal cancer.

And then, finally, as far as disease is concerned as you might expect given all of the infections I’ve been telling you about, that there is a lot of disease. So if you do anal Pap smears in HIV positive men, about 75% of the people who are the most immune suppressed have an abnormal anal Pap as do about 20% of HIV negative MSM.

And in the age range you see again it stays pretty constant. The only thing that we’re starting to see is a bit of an uptake of high-grade disease as you might expect when people start to get older. And this is the group that’s probably at highest risk for developing anal cancer.

And going back to the population based data here on the right for anal intraepithelial neoplasia, a third of the HIV negative men have it. Almost 60% of the HIV positive individuals have it with nearly one-half having high-grade disease. So this is a very, very common and disturbing problem.

And then finally with respect to the women, since I told you we see more anal HPV infection than cervical, you may wonder if we see more AIN in the women and the answer is yes. In the Women’s Interagency HIV study we found that 21% had AIN compared to 13% with CIN and that was true but whether you’re HIV positive or negative, where there was more AIN in the HIV negative women as well then compared with CIN.

So what should we be doing about this? We have two areas where we need to be thinking about the impact, potentially, of vaccination. One is prevention of disease in men and the other is to consider men as partners in the spread of HPV with their consequences for women. And so if you think about men as vectors of HPV infection I want to emphasize as a man that this is a sexually transmitted disease. Men cannot be considered the sole vectors, that wouldn’t work. So it really is a bilateral relationship here. But if you think about the men as a potential source, sexual contact is necessary for transmission. There is a number of studies showing a strong and consistent association between the number of recent and lifetime male partners with detection of HPV in women. The risk of cervical cancer is clearly associated with behavior on the part of the men in terms of presence of genital HPV infection and number of extramarital partners. And the male circumcision rate also influences the risk of cervical cancer since we think that influence is the risk of penile infection.

So the public health rationale for gender neutral vaccination, that means both men and women, include the following: the fact that men transmit HPV to women; that gender-neutral vaccination may lead to more rapid and complete reduction in the burden of disease in women, and the reason for that is that if all women were vaccinated than this would be moot, we wouldn’t need to vaccinate the men but we know that only a proportion of the women who were potentially eligible for vaccination are actually getting vaccinated, at least right now. And as you might expect that if you look at the benefits of adding males to vaccination programs the higher the vaccination rate in women, the less cost-effective it would be. But if, for example, only half of the women or less are being vaccinated than vaccinating males in cost-effectiveness studies do show that adding men to the program may be cost-effective.

So, of course, the question is does the vaccine work in boys? As you know the skin surfaces that we’ve been talking about in the men are different from the ones you’ve heard about in women. And all I can tell you is that the bridging studies that Dr. Cox referred to in which the immunogenicity of the vaccine, not the efficacy, but the immunogenicity was studied in young boys, did show that the prepubertal boys and boys around the time of puberty produced titers that were as good if not better than similarly age girls. So the vaccine from that point of view should be immunogenic. And then the data showing good efficacy in external vulvar condyloma, which is a skin surface similar to what you might get on the penis, offer a lot of hope that we’ll see good efficacy on the penis as well. So we’re optimistic that the vaccine will work well in men. There is a big study that is going on now, which some data are going to be available soon on the efficacy of the vaccine in men and we’ll see how well it works in the penis, and in the sub-study of MSM to see how well it works to prevent anal HPV inspection.

So just to summarize then, what I’ve been trying to convey is that HPV infection leads to substantial disease burden in men. That HPV infection is transmitted from men to women leading to a substantial disease burden in women. That the immunogenicity data and similarity of the biology of HPV associated disease in men and women suggest that the vaccine may be effective to prevent HPV in men, we’ll see soon. The benefits would include not only reduction in disease in men but enhanced herd immunity to reduce disease in women. So it all sounds good. And hopefully we’ll have some results pretty soon in the men to see if our hypotheses are correct. And with that I’d like to thank you very much for your attention.